Facility Design and Mode of Operation

Successful elimination and minimization of sources and vectors of contamination rests with their identification and, largely, with facility design. The identification of sources and vectors has been addressed, but how are they to be eliminated or minimized? The answer to this question mainly lies in GMPs for the control of materials flow, people flow, air flow, and water.

Manufacturing facilities should be designed to ensure that materials are handled in a manner that affords control of microbiological- and cross-contamination. In the author's experience, cross-contamination is mainly a problem of powders, dusts, and solids. With liquids, ointments and semisolids, microbiological contamination is a far greater source of genuine problems.

Everything that comes into a facility will bring microorganisms with it. The first principle of control is to restrict the access points, preferably to one location for all incoming materials, and confine the contaminants as far as possible to this location. Much of what is effective in confining contaminants to incoming warehouses is achieved by negotiation with suppliers, with regard to delivery.

For instance, wooden pallets should not proceed beyond warehousing because they are potent sources of contamination. Cardboard boxes should be wrapped or shrouded in plastic to minimize the contamination carried on them. It is almost inevitable that cardboard boxes will be moved into the facility beyond the incoming warehouse: their contents should be supplied in inner plastic wrappers, allowing the cardboard to be discarded well away from any areas in which product may be exposed. A microbiologically well-designed facility has simple and clearly designated routes of movement of materials from warehousing to production — from minimally to better-controlled areas, with "dirty" wrappings shed at designated locations along the way.

Contamination from people is carried on shoes, clothing, hair and skin. The access of personnel to a facility for manufacturing pharmaceutical preparations must be controlled. There are innumerable variations on how personnel access control to facilities may be achieved, and to what extent control is necessary. The most stringent level is to have all personnel change out of their street clothes into a company uniform with dedicated footwear on entry to the facility. Thereafter, it may be necessary to change clothes again or to put on overalls for entry to designated manufacturing areas or other areas where product is exposed.

Secondary changing would be expected before entry into areas for the manufacture of liquids, ointments and semisolids; but probably not for filling areas (provided the filling machines have some localized protection). Facilities must be designed to accommodate changing rooms appropriate to the need for product protection.

Personnel working in the manufacture of liquids, ointments and semisolids should wear long-sleeved overalls, head covers, and cover up excessive facial hair (such as beards, moustaches or sideburns). Ideally they should wear gloves when they are handling the preparation, its raw materials, and equipment that comes into contact with the product.

Air is a significant potential source and vector of microbiological contamination to liquids, ointments and semisolids; particularly to inhalations where high microbiological standards are of greatest importance. This is due to the difficulty in treating Gram-negative infections of the lungs with antibiotics. The potential of air as a contaminant must be controlled by:

• Filtration

• Dilution through recirculation

• Positive pressure differentials

• Intact walls, closed doors and air locks

The air supply to manufacturing areas for liquids, ointments and semisolids should equally be filtered. The rating of filters needed to control contamination from air supplies to nonsterile manufacturing areas is not defined in the codes of GMP. Many manufacturers choose HEPA filtration, although HEPA filters are primarily intended for controlling the quality of air to sterile manufacture, and in sensitive applications in the electronics industry.

The necessity for HEPA filtration of air to topicals and oral liquids manufacturing applications depends on the quality of incoming environmental air and the prefiltration deployed. While HEPA filters are the only type with the significant retention of 0.3-^m particles (the approximate size of individual microorganisms), most airborne microorganisms are in fact carried in clusters on far bigger dust particles (about >5 ^m in size) and will therefore be retained by less strictly rated filters. It is very unusual to find inhalations manufacturing areas for which the air supply is not passed through HEPA filters.

It is rarely economic, unless other factors such as cross-contamination come into play, to find single-pass air-filtration systems. It is more usual for filtered air to be recirculated through the filters, thus imposing a less stringent burden on the filters and diluting the challenge. Up to 80% of air is recirculated, sometimes more.

The rate of supply of air to manufacturing areas should provide airflow in an outward direction from the area requiring protection from airborne contamination; microorganisms are not equipped to move upstream against an airflow. Outward airflows are normally monitored through positive pressure differentials.

Recommendations in codes of GMP, such as 15 Pascals for sterile-area differentials, typically originate from experience past success rather than from any exact science. Ten Pascals is probably adequate for most nonsterile applications.

The final area of controlling contamination from air is the fabric and design of the facility. Air can be lost through walls if they are pervious, so impervious finishes are best used. If doors are opened, all positive pressure may be lost and contaminated air may enter an area that should be protected. Doors should be self-closing; and if the protection from airborne contamination is deemed important enough, they should be protected by air locks.

Water is probably the most significant combined source and vector for microbiological contaminants. Its control should be included in the design and operation of all facilities.

All water entering manufacturing facilities must be of potable quality, or must be treated (e.g., by chlorination) to bring it to these standards. This quality of water may be used for many applications, from drinking to equipment cleaning. If incoming water from a municipal supply fails to meet the customary microbiological standard of not more than 500 cfu per ml, little can be done to improve its quality except re-treatment in the pharmaceutical facility.

Ingredient water for pharmaceutical purposes must always involve some treatment of source water, to bring it to the pharmacopoeial standards for either purified water or for water for injection. Purified water is required for liquids, ointments and semisolids.

Typical treatments for preparation of purified water (e.g., deionization, reverse osmosis) improve the chemical quality of the water, but may not necessarily improve its microbiological quality. In certain circumstances, such treatments may actually lead to poorer microbiological quality.

Where distillation is used for the preparation of water for injection, the high temperatures involved give water for injection an intrinsically high microbiological quality.

Feed water pretreated with chlorination is used in processes for the preparation of purified water. Unfortunately, the presence of high concentrations of chlorine ions can impair chemical purification processes; excess chlorine is usually removed by passage of the rechlorinated water through carbon filters. Carbon filters, unless kept in good condition by recirculation of water and periodic backwashing, can themselves become a source of contamination. This may then be carried into the purified water-distribution system.

The microbiological quality of the water in systems for storage and distribution of purified water is maintained in a variety of ways. The water must always be kept in constant recirculation to prevent formation of biofilms on the inner surfaces of tanks and pipework. Valves and take-off points must be of the sanitary type. If the water remains stagnant there is an opportunity for microorganisms to multiply. The complete system must be periodically sanitised. This is usually best and most economically effected by using high temperatures, either at steam temperatures, or by recirculation above 80°C at intervals dictated by experience. To achieve these temperatures, heat exchangers should be included in the design of the distribution system.

Many purified water distribution systems include ultraviolet light stations to control microbiological quality. Care must be taken to ensure that these systems are working properly; it is quite possible that they only damage microorganisms, rather than killing them. Special media (e.g., R2A), low temperatures (e.g., 20-25°C), and extended times (e.g., 10-14 days) of incubation should be included in the validation of new systems to address this potential. The phenomenon of viable but non-culturable microorganisms after ultraviolet treatment and in general is well known.2,5,6 Water-borne types are particularly difficult to culture; their mode of growth is not suited to the high concentrations of nutrients found in most general purposes media, nor are they suited to growing at temperatures above 30°C, and certainly not within a couple of days.

Some purified water distribution systems are operated at low (<15°C) or high (>40°C) temperatures to maintain high microbiological standards, but generally acceptable standards can be achieved more economically.

The other area of concern regarding water in facility design is drainage. Where water is left to stand, Pseudomonas spp. do not only survive but proliferate. Water should not be permitted to stand on equipment (particularly in crannies and crevices), on floors, or in sinks and wash-bays. Contamination spreads with water, forming films over surfaces and on the hands and clothing of personnel. Waterborne contaminants may be aerosolized by vibrations or when water falls more than a few centimetres. To restrict the opportunity for contamination from water, there should be air breaks of about 5 cm installed between equipment drains and tun dishes leading to foul drains.

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